Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
BMC Cardiovasc Disord. 2014 Jan 14;14:6. doi: 10.1186/1471-2261-14-6.
The Ryanodine receptor 3 gene (RYR3) encodes an intracellular calcium channel that mediates the efflux of Ca2+ from intracellular stores. Two single-nucleotide polymorphisms (SNPs) in the RYR3 gene have been shown to associate with stroke (rs877087) and carotid intima-media thickness (rs2229116) in two independent genome-wide association studies (GWAS) in Caucasian. We investigated the effect of these two SNPs as well as the 31.1 kilobases spanning region on atherosclerosis in Japanese population.
Atherosclerotic severity was assessed by carotid artery (n = 1374) and pathological atherosclerosis index (PAI) (n = 1262), which is a macroscopic examination of the luminal surfaces of 8 systemic arteries in consecutive autopsy samples. 4 tag SNPs in the 31.1 Kb region, rs877087, rs2132207, rs658750 and rs2229116, were genotyped and haplotypes were inferred to study the association with atherosclerotic indices.
rs877087 and rs2229116 were associated with PAI (OR = 2.07 [1.04-4.12] (95% CI), p = 0.038; and OR = 1.38 [1.02-1.86], p = 0.035, respectively). rs2229116 was also associated with common carotid atherosclerosis (OR = 1.45 [1.13-1.86], p = 0.003). The risk allele of rs2229116 was opposite from the original report. The haplotype block of this 31.1 Kb region was different between Caucasian and Japanese. Haplotype analysis revealed that only TAGG haplotype was associated with PAI (OR = 0.67 [0.48-0.94], p = 0.020) and atherosclerosis of common carotid artery (OR = 0.75 [0.58-0.98], p = 0.034).
rs877087 and rs2229116 of RYR3 gene are associated with atherosclerosis severity in Japanese. The functional difference caused by rs2229116 needs to be investigated.
Ryanodine 受体 3 基因（RYR3）编码一种细胞内钙离子通道，介导细胞内储存的 Ca2+ 外流。两项独立的全基因组关联研究（GWAS）表明，RYR3 基因中的两个单核苷酸多态性（SNP）与中风（rs877087）和颈动脉内膜-中层厚度（rs2229116）有关。我们在日本人群中研究了这两个 SNP 以及跨越 31.1 千碱基对的区域对动脉粥样硬化的影响。
通过颈动脉（n=1374）和病理动脉粥样硬化指数（PAI）（n=1262）评估动脉粥样硬化严重程度，PAI 是对连续尸检样本中 8 条系统性动脉管腔表面的宏观检查。对 31.1 Kb 区域的 4 个标签 SNP(rs877087、rs2132207、rs658750 和 rs2229116)进行基因分型，并推断单体型以研究与动脉粥样硬化指数的关联。
rs877087 和 rs2229116 与 PAI 相关（OR=2.07[1.04-4.12]（95%CI），p=0.038；OR=1.38[1.02-1.86]，p=0.035）。rs2229116 也与颈总动脉粥样硬化有关（OR=1.45[1.13-1.86]，p=0.003）。rs2229116 的风险等位基因与原始报告相反。该 31.1 Kb 区域的单体型块在白种人和日本人之间存在差异。单体型分析表明，只有 TAGG 单体型与 PAI（OR=0.67[0.48-0.94]，p=0.020）和颈总动脉粥样硬化（OR=0.75[0.58-0.98]，p=0.034）有关。
RYR3 基因的 rs877087 和 rs2229116 与日本人动脉粥样硬化严重程度有关。rs2229116 引起的功能差异需要进一步研究。
